Tumor cell -TAM Paracrine Signaling in Breast Cancer

乳腺癌中的肿瘤细胞 -TAM 旁分泌信号传导

• 批准号: 10583793
• 负责人: Elizabeth S. Yeh
• 金额: $ 45.64万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-13 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10583793
• 关键词: 4T1; Affect; Agonist; Antineoplastic Agents; Attenuated; Back; Breast Cancer Model; Breast Cancer cell line; Categories; Cells; Chemoresistance; Clinical; Data; Diagnosis; Disease; Down-Regulation; Endowment; Epidermal Growth Factor Receptor; Exhibits; Extracellular Matrix; FDA approved; Flow Cytometry; Genetic Transcription; Goals; Grant; Human; Immune; Immune checkpoint inhibitor; Immunohistochemistry; Immunosuppression; Impairment; Individual; Infiltration; Inflammatory; Interleukin 4 Receptor; Interleukin 6 Receptor; Interleukin-4; Invaded; Knowledge; Lymphocytic Infiltrate; Macrophage; Macrophage Activation; Mammary Neoplasms; Measures; Mediating; Methods; Modeling; Neoplasm Metastasis; Paracrine Communication; Patients; Phenotype; Phosphorylation; Phosphotransferases; Play; Population; Primary Neoplasm; Production; Prognosis; Receptor Signaling; Recovery; Regulation; Research; Role; Sampling; Shapes; Signal Pathway; Signal Transduction; Stat3 Signaling Pathway; Testing; Time; Tumor Angiogenesis; Tumor Biology; Tumor Promotion; Tumor-Infiltrating Lymphocytes; Tumor-associated macrophages; Up-Regulation; Work; antitumor effect; cell type; improved; in vivo; in vivo Model; knock-down; loss of function; malignant breast neoplasm; mammary; mouse model; neoplastic cell; paracrine; recruit; response; single-cell RNA sequencing; small hairpin RNA; therapeutic evaluation; transcription factor; triple-negative invasive breast carcinoma; tumor; tumor microenvironment; tumorigenic

ABSTRACT Immune checkpoint inhibitors are FDA approved for metastatic triple negative breast cancer (TNBC) and work well for patients with high levels of tumor infiltrating lymphocytes (TIL), but for the majority of BC patients, these agents are ineffective. Continued research is needed to elucidate the interplay between tumor cells and the diverse immune cell populations within the primary TME, and how this interaction shapes tumor biology. Tumor- associated macrophages (TAM) represent one of the most abundant immune components in BC TME and exhibit a robust and unique influence on the disease. High levels of TAM infiltration are associated with poor prognosis in BC. TAMs play a critical role in a wide range of pro-tumorigenic, pro-metastatic activities including tumor angiogenesis, extracellular matrix (ECM) remodeling, immunosuppression, and chemoresistance. How to surmount TAM infiltration and function in order to activate a potent anti-tumorigenic and anti-metastatic response represents a gap in knowledge for the BC field. TAMs most closely resemble M2-polarized type macrophages and exhibit some overlapping functions between the categories. TAMs are a highly heterogeneic, plastic cell population endowed with tumor-promoting functionality measured by the overall abundance of M2 vs M1 markers. TAM polarization and immunosuppressive capacities are dependent upon where these cells are located and what signals are received within the TME. Whereas M2-like polarization is considered pro-tumorigenic, M1- like polarization is associated with inflammatory, anti-tumor effects and improved prognosis. Tumor cells generate paracrine signals that recruit and regulate TAM function. In turn, TAMs produce signals that affect the metastatic potential of tumor cells. Given the clear pro-tumor and metastatic roles of TAMs, it seems evident that identifying ways to abrogate pro-tumorigenic M2-like responses and promote anti-tumorigenic M1-like responses in BC will be clinically advantageous. However, effective strategies remain elusive. Our proposal introduces a new strategy to target a kinase called HUNK that has the potential to be more advantageous than strategies that directly target TAMs. Targeting HUNK will have a multifaceted effect by not only halting pro-tumor/metastatic tumor intrinsic signaling but also fundamentally changing the “feed forward” paracrine loop between tumor cells and TAMs.

抽象的 免疫检查点抑制剂已获 FDA 批准用于治疗转移性三阴性乳腺癌 (TNBC)，并且有效 对于肿瘤浸润淋巴细胞 (TIL) 水平高的患者来说效果很好，但对于大多数 BC 患者来说，这些 需要继续研究来阐明肿瘤细胞和肿瘤细胞之间的相互作用。 原发性 TME 内不同的免疫细胞群，以及这种相互作用如何塑造肿瘤生物学。 相关巨噬细胞 (TAM) 是 BC TME 中最丰富的免疫成分之一，并表现出 高水平的 TAM 浸润与不良预后相关。 在 BC 中，TAM 在包括肿瘤在内的多种促肿瘤、促转移活性中发挥着关键作用。 血管生成、细胞外基质 (ECM) 重塑、免疫抑制和化疗耐药性。 克服 TAM 浸润和功能，以激活有效的抗肿瘤发生和抗转移反应 代表了 BC 领域的知识空白，TAM 最类似于 M2 极化型巨噬细胞。 TAM 是一种高度异质的塑料细胞，并且在这些类别之间表现出一些重叠的功能。 通过 M2 与 M1 的总体丰度衡量，具有促肿瘤功能的人群 TAM 极化和免疫抑制能力取决于这些细胞的位置。 以及 TME 内接收到什么信号，而 M2 样极化被认为是促肿瘤发生的，M1- 是这样的。 极化与炎症、抗肿瘤作用和改善肿瘤细胞的预后有关。 产生旁分泌信号来募集和调节 TAM 功能，而 TAM 又会产生影响 TAM 功能的信号。 鉴于 TAM 具有明确的促肿瘤和转移作用，似乎很明显： 确定消除促肿瘤 M2 样反应并促进抗肿瘤 M1 样反应的方法 BC 在临床上将是有利的，但是，我们的建议仍然难以捉摸。 针对名为 HUNK 的激酶的新策略可能比其他策略更具优势 直接靶向 TAM 将产生多方面的效果，不仅可以阻止促肿瘤/转移。 内在的肿瘤信号传导，但也从根本上改变了肿瘤细胞之间的“前馈”旁分泌环路 和 TAM。